Inhibition of virally encoded protease of the human immuno deficiency virus results in the production of immature, non-infectious virions. HIV protease specifically process gag and gag-pol viral poly proteins to yield the viral structural proteins, as well as the viral enzymes reverse transcriptase, integrase and protease. Betulinic acid derivatives were known as first of a new class of anti-retroviral agents that inhibit HIV-1 replication by disrupting virus maturation (Science 1983, 220, 868-871; N. Eng. J. Med. 1984, 311, 1292-1297). For example, Bevirimat as a compound with a novel mechanism of action (J. Nat. Prod. 199457(2):243-7; J. Med. Chem. 1996, 39(5), 1016). Further studies shown that bevirimat acts by disrupting gag processing (Proc. Natl. Acad. Sci. USA 2003, 100(23):13555-60; Antimicrob. Agents. Chemother. 2001, 45 (4), 1225-30; J. Virol., 2004, 78(2): 922-9; J. Biol. Chem. 2005, 280 (51): 42149-55; J. Virol. 2006, 80 (12): 5716-22) and to be a first-in-class maturation inhibitor with a potent activity against HIV-1. Due to this novel mechanism of action, some of these derivatives did show potent activity against HIV-1 strains that are resistant to currently approved classes of anti-retroviral agent.
Our co-pending PCT application PCT/IB2010/001677 filed on 5 Jul. 2010 discloses certain compounds of betulinic acid derivatives and is herein incorporated by reference. These compounds are highly active against HIV strains of different subtypes. Even though, said application discloses generically pharmaceutically acceptable salts of said compounds, specific pharmaceutically acceptable salts of compounds of present invention are not disclosed in PCT/IB2010/001677. Further, no information is provided, in relation to crystalline forms of disclosed compounds, particularly salts thereof Compounds disclosed in PCT/IB2010/001677 are free acids. Therefore there is need for preparing pharmaceutically acceptable salts of these compounds which have physical and chemical properties suitable for using pharmaceutical formulations.
Further, in the manufacturing of drug compositions, it is important that a reliable, reproducible and constant plasma concentration profile of drug is provided following administration to patients. Chemical stability, salt state stability and shelf life of the active ingredients are also very important factors. The drug substances and compositions containing it should preferably capable of being effectively stored over appreciable periods of time without exhibiting a significant change in the active components physiochemical characteristics like chemical composition, density, hygroscopicity and solubility. Moreover it is also important to be able to provide drug in a form which is as chemically pure as possible. If possible, it is desirable to enhance biological properties like bioavailability by improving dissolution properties. One among the numerous pharmaceutical approaches to achieve the above said properties is preparing pharmaceutically acceptable salts.